Angiogenesis is a critical feature of malignant tumor growth and metastasis and anti-angiogenesis targeting has improved survival in numerous solid tumor malignancies. However, anti-angiogenesis therapy cannot be expected to be equally effective across tumor types, sizes, locations, stages and grades. The utility of antiangiogenesis treatment with bevacizumab in breast cancer has been hotly debated in the press and scientific forums based on recent clinical trial data, however, current clinical recommendations affirm bevacizumab as an appropriate therapeutic option in combination with paclitaxel for metastatic breast cancer. In this proposal, we hypothesize that the identification of breast cancers with active neoangiogenesis will enhance the efficacy of targeted antiangiogenesis therapy. We contend that a compelling clinical need exists for quantitative molecular imaging to identify and follow breast cancer patients likely to respond to anti-angiogenic treatment. Although anti-VEGF monoclonal and receptor tyrosine kinase inhibitor drugs are approved in the clinic as antiangiogenic treatments, costing >$100,000/patient and exhibiting well documented adverse effects, alternative theranostic nanomedicine approaches specifically targeting neovessel endothelium with minute doses of highly potent, compounds, such as fumagillin, may represent an improved approach. We hypothesize that the efficacy of theranostic nanoparticles targeted to neovessel endothelium will reflect tumor dependence on angiogenesis for progression. We further hypothesize that the benefits of theranostic antiangiogenic nanoparticles can be enhanced using non-cross resistant anti-angiogeneic compounds, such as amino-bisphosphonates that have direct and indirect cytotoxic effects on neoangiogenesis and tumor-recruited myeloid cells that secrete pro-angiogeneic factors. Osteoprotegerin (OPG) receptor activator of nuclear factor-kB (RANK) and RANK ligand (RANKL) pathway plays a central role in bone destruction through osteoclast differentiation and osteolysis due to bone metastasis, which occurs in 70% of women with breast cancer. While amino-bisphosphonates (N-BP) and RANKL-Ab disrupt the OPG-RANK-RANKL system, inhibiting osteoclast formation or function, they can also induce apoptosis and antiangiogenesis in some cancers, including breast. We hypothesize that acute nanomedicine-based antiangiogenic therapy combined with N-BP treatment would be effective as pre-adjuvant and maintenance therapy. The specific aims of this study are: Aim 1. Compare the effectiveness of anti-angiogenesis and tumor progression with bevacizumab versus av[unreadable]3-fumagillin-prodrug nanoparticles in soft tissue, visceral, and metastases and correlate treatment response with pretreatment tumor size and neovasculature character. Aim 2. Determine the efficacy of N-BP in combination with theranostic nanoparticles targeted to neovessel endothelium on breast cancer tumor growth, metastasis and survival. PUBLIC HEALTH RELEVANCE: Angiogenesis, new vessel formation, is a critical feature of malignant tumor growth and metastasis. However, as evidenced recently for breast cancer, anti-angiogenesis therapy cannot be expected to be equally effective across tumor types, sizes, locations, stages and grades. We hypothesize that antiangiogenic therapy and long-term survival could be significantly enhanced in breast cancer given proper patient selection. We contend that a compelling need exists for quantitative nanomedicine approaches to identify, treat and follow patients likely to respond to treatment. Although antiangiogenic therapy is currently used transiently in combination with chemotherapy, we suggest that the acute benefits of this approach could be maintained effectively for soft, visceral, and bone cancers with compounds exerting milder indirect effects on neovascular expansion, such as amino-bisphosphonates.